Study Shows How Eye Cells Die when Exposed to Lead

A new study designed to find out why cells in the eye die when exposed to lead may provide novel therapies for retinal damage caused by injury or diseases such as diabetes and retinitis pigmentosa.

The study, published in the Feb. 4 issue of the Proceedings of the National Academy of Sciences, focused on identifying how low-level lead exposure during development in mice injures and eventually kills rod-shaped photoreceptor cells, or rods, in the eye.

Rods are cells in the eye that help humans see in dim light. The other type of photoreceptors, or light-gathering cells, called cones are responsible for color and spatial vision. Cones are used primarily in daylight and for activities such as reading.

“Lead is a toxicant, and when the retina is exposed to lead, we found that it triggers a chain of biochemical events that leads to the selective apoptotic death of rod photoreceptors,” says Donald A. Fox, professor of vision sciences, biology and biochemistry, and pharmacology at the University of Houston and principal investigator of the study.

“The human eye contains so many rods that you can lose about 20 percent of them and not have much functional loss of vision,” Fox says. “But for people who need to see clearly at night, such as truck drivers, or for people who are losing their rods due to disease or injury, finding a way to prevent the rods from dying is important.”

In June 2002, Fox and his colleagues published a study showing that 7- to 10-year-old children whose mothers had elevated levels of lead in their blood during the first trimester of pregnancy developed retinal abnormalities, specifically in their rods (Investigative Ophthalmology & Visual Science, June 2002, Vol. 43. No. 6). A study currently underway with the same children is assessing whether lead exposure during development affects the eye’s cones as well.

“We can’t tell whether the rods actually die, because these are living children, but there are unique functional abnormalities in these children. They may have visual system deficits that eventually could lead to permanent retinal alterations and learning problems,” Fox says. “We’re not sure what the functional basis of this observation is, and we hope to study it further.”

According to the Centers for Disease Control and Prevention, the acceptable level of lead in the blood is 10 micrograms per deciliter. The CDC estimates that about 900,000 U.S. children under age 6 have blood lead levels at that level or higher. The children in Fox’s ongoing study live in and around Mexico City and had blood lead levels of 6 micrograms per deciliter or above.

Fox’s latest animal study in PNAS sheds some light on the mechanisms responsible for lead-mediated cell death, or apoptosis, in the eye, and may suggest possible treatment options for patients suffering from various forms of retinal degeneration.

The key to most cell death is a structure within each cell called the mitochondrion, which is known primarily as the central component responsible for generating energy for the cell. But when a cell is damaged, the mitochondria become the “central executioners,” releasing proteins sequestered within them that are death signals for the cell.

Here’s how Fox believes lead-mediated cell death occurs:

When the rod cells in the eye are exposed to lead, it triggers an increase in the amount of lead and calcium entering the cell. A higher level of calcium within the mitochondria sensitizes the mitochondria to interact with a

“death factor” protein produced by the cell called Bax. Fox says Bax seems to cause channels, or pores, in the mitochondria to open up and release yet another “death factor” protein called cytochrome c. This protein eventually causes changes that wreak havoc on the cell’s nucleus, destroying its DNA and killing the cell.

“The mitochondrion is like a fort that’s tightly guarded,” Fox explains. “Normally things don’t get out. But Bax appears to open up the gate to the fort, letting cytochrome c escape.”

Guy Perkins, Fox’s colleague at the National Center for Microscopy and Imaging Research at the University of California, San Diego, produced detailed images of the animals’ rod mitochondria for the study.

“We found the lead-exposed eyes had more of these ‘gates,’ which are called contact sites, opened up along the surface of the mitochondria than the non-exposed eyes, and we believe these contact sites are associated with the cytochrome c release,” Fox says.

The researchers also found that an excess of an anti-death protein called Bcl-xL completely blocked the death of the eye’s rod cells and maintained normal mitochondrial function in the rods throughout adulthood.

“All cells produce anti-death proteins like Bcl-xL, and normally when they combine with Bax, it prevents Bax from triggering cell death. Too much Bax results in cell death,” Fox says.

“But these transgenic mice were genetically engineered to produce excessive amounts of Bcl-xL in their rod cells. We found that these overexpressed levels of Bcl-xL blocked the Bax from associating with the mitochondria, as well as blocked the increased formation of contact sites and release of cytochrome c from the mitochondria. If the cytochrome c can’t get out of the mitochondria, the cells do not die.”

The research results suggest possible avenues for treatment of some eye disorders.

“For people whose rods are dying, such as in retinitis pigmentosa, or diabetes, or immediately after a traumatic eye injury, if you can get higher levels of this anti-death protein, Bcl-xL, or one like it, into the eye, it could help prevent cell death. It has relevance for therapies for a wide variety of retinal degenerations,” Fox says.

The key to Fox’s experiment was to expose the mice to lead levels that are relevant to environmental levels of lead that humans might be exposed to. “Previous animal models have used lead levels that were not consistent with the low-level lead exposure and slow cellular degeneration that actually occurs in human disease,” he says.

Fox’s research is funded by the National Institutes of Health and the University of Houston.
SOURCE: Fox, 713-743-1964; email: dafox@uh.edu

The University of Houston, Texas’ premier metropolitan research and teaching institution, is home to more than 40 research centers and institutes and sponsors more than 300 partnerships with corporate, civic and governmental entities. UH, the most diverse research university in the country, stands at the forefront of education, research and service with more than 34,400 students.

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